2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCTGCCGCTGCT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_000939.4(POMC):c.297_298insAGCAGCGGCAGCAGCGGC(p.Ser94_Gly99dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,557,926 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

POMC
NM_000939.4 inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.649

Variant links:

Genes affected

POMC (HGNC:9201): (proopiomelanocortin) This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jan 2016]

POMC links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000889 (135/151892) while in subpopulation AMR AF= 0.00164 (25/15282). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POMC	NM_000939.4 linkuse as main transcript	c.297_298insAGCAGCGGCAGCAGCGGC	p.Ser94_Gly99dup	inframe_insertion	3/3	ENST00000395826.7
POMC	NM_001035256.3 linkuse as main transcript	c.297_298insAGCAGCGGCAGCAGCGGC	p.Ser94_Gly99dup	inframe_insertion	4/4
POMC	NM_001319204.2 linkuse as main transcript	c.297_298insAGCAGCGGCAGCAGCGGC	p.Ser94_Gly99dup	inframe_insertion	4/4
POMC	NM_001319205.2 linkuse as main transcript	c.297_298insAGCAGCGGCAGCAGCGGC	p.Ser94_Gly99dup	inframe_insertion	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7 linkuse as main transcript	c.297_298insAGCAGCGGCAGCAGCGGC	p.Ser94_Gly99dup	inframe_insertion	3/3	2	NM_000939.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000889

AC:

135

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.000422

AC:

AN:

153946

Hom.:

AF XY:

0.000395

AC XY:

AN XY:

83598

show subpopulations

Gnomad AFR exome

AF:

0.00131

Gnomad AMR exome

AF:

0.000707

Gnomad ASJ exome

AF:

0.000957

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000214

Gnomad FIN exome

AF:

0.000128

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.000358

AC:

504

AN:

1406034

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

264

AN XY:

694674

show subpopulations

Gnomad4 AFR exome

AF:

0.00161

Gnomad4 AMR exome

AF:

0.00133

Gnomad4 ASJ exome

AF:

0.00143

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000399

Gnomad4 FIN exome

AF:

0.0000827

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.000889

AC:

135

AN:

151892

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.00143

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.00285

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This variant, c.280_297dup, results in the insertion of 6 amino acid(s) of the POMC protein (p.Ser94_Gly99dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs10654394, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with extreme obesity but a second variant was not observed (PMID: 9768693). This variant is also known as the 18bp insertion between codon 73 and 74. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2017	- -

Obesity due to pro-opiomelanocortin deficiency;C4054476:Inherited obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over